Processes for preparing benzimidazole thiophenes

ABSTRACT

A process for preparing benzimidazole thiophenes including 5-{6-[(4-methylpiperazin-1-yl)methyl]-1H-benzimidazol-1-yl}-3-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxamide.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is filed pursuant to 35 USC 371 as a United StatesNational Phase Application of International Patent Application SerialNo. PCT/US2008/067867 filed on Jun. 23, 2008, which claims priority from60/946,209 filed on Jun. 26, 2007 in the United States.

BACKGROUND OF THE INVENTION

The present invention relates to a novel process for preparingbenzimidazole thiophene compounds. Benzimidazole thiophene compoundswhich may be prepared using the processes of the present invention aredescribed in PCT Publication Nos. WO2004/014899, WO2007/036061 andWO2007/030359, all to SmithKline Beecham Corp. Pharmaceuticalformulations and therapeutic uses and other processes for thepreparation of such compounds are also disclosed therein.

A regioselective synthesis of benzimidazole thiophene compounds isdisclosed in PCT Publication No. WO2007/030366 to SmithKline BeechamCorp.

In particular,5-{6-[(4-methylpiperazin-1-yl)methyl]-1H-benzimidazol-1-yl}-3-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxamideand processes for its preparation are described in PCT Publication Nos.WO2007/036061 and WO2007/030359, both to SmithKline Beecham Corp.

BRIEF SUMMARY OF THE INVENTION

As a first aspect, the present invention provides a process forpreparing a compound of formula (I):

-   -   wherein:    -   R¹ is OH, O-alkyl or NH₂;    -   R² is alkyl;    -   R³ is F, Cl, Br, alkyl or haloalkyl,    -   a is 0 or 1    -   R⁴ is selected from F, Cl, Br, alkyl, haloalkyl, alkenyl,        cycloalkyl, cycloalkenyl, phenyl, Het, —C(O)R⁷, —C(O)NR⁷R⁸,        —OR⁷, —O-phenyl, —O-benzyl, —O-Het, —O—R⁶-Het; —NR⁷R⁸,        —N(R⁷)C(O)R⁸, —N(R⁷)Het, —N(R⁷)S(O)₂R⁸, —N(R⁷)—R⁶—S(O)₂R⁸ and        —CN;        -   Het is selected from heterocycles and heteroaryls, wherein            said heterocycle or heteroaryl may optionally be substituted            with one or two substituents selected from halo, alkyl,            haloalkyl, oxo, OH, O-alkyl, alkylene-OH, and            alkylene-SO₂-alkyl;    -   R⁵ is selected from —NR⁷R⁸ and N-heterocycles, wherein said        N-heterocycle may optionally be substituted with one or two        substituents selected from halo, alkyl, haloalkyl, oxo, OH,        O-alkyl, alkylene-OH and alkylene-SO₂-alkyl;    -   R⁶ is alkylene; and    -   each R⁷ and R⁸ are the same or different and are each        independently selected from H and alkyl    -   or a pharmaceutically acceptable salt thereof.

The process comprises the steps of:

-   a) reacting a compound of formula (II):

-    wherein Hal is halo;-   with an amine of formula H—R⁵ to prepare a compound of formula (III)    or a salt thereof:

-   b) cross-coupling the compound of formula (III) or a salt thereof    with a compound of formula (IV) or a salt thereof:

-   to prepare a compound of formula (V) or a salt thereof:

-   c) reducing the compound of formula (V) or a salt thereof to prepare    a compound of formula (VI) or a salt thereof:

-   d) cyclizing the compound of formula (VI) or a salt thereof to    prepare a compound of formula (I-A) or a salt thereof:

-    and-   e) optionally converting the ester compound of formula (I-A), or    salt thereof, to a corresponding amide compound of formula (I-B):

As a second aspect, the present invention provides a process forpreparing a compound of formula (X):

-   -   wherein:    -   R³ is F, Cl, Br, alkyl or haloalkyl;    -   R¹⁰ is H or alkyl,    -   or a pharmaceutically acceptable salt thereof.

The process comprises the steps of:

-   a) reacting 3-bromo-5-nitrobenzaldehyde:

-   with an amine of formula:

-   to prepare a compound of formula (III-a) or a salt thereof:

-   b) cross-coupling the compound of formula (III-a) or a salt thereof    with a compound of formula (IV-a) or a salt thereof:

-   in the presence of a palladium catalyst to prepare a compound of    formula (V-a) or a salt thereof:

-   c) reducing the compound of formula (V-a) or a salt thereof to    prepare a compound of formula (VI-a) or a salt thereof:

-   d) cyclizing the compound of formula (VI-a) or a salt thereof in the    presence of an orthoester and an acid catalyst to prepare a compound    of formula (IX) or a salt thereof:

-    and-   e) converting the ester compound of formula (IX), or salt thereof to    the amide compound of formula (X).

As a third aspect, the present invention provides a process forpreparing5-{6-[(4-methylpiperazin-1-yl)methyl]-1H-benzimidazol-1-yl}-3-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxamide:

The process comprises the steps of:

-   a) reacting 3-bromo-5-nitrobenzaldehyde:

-   with N-methyl piperazine:

-   to prepare 1-[3-bromo-4-nitrophenyl)methyl]-4-methylpiperazine or a    salt thereof, particularly the HCl salt thereof:

-   b) cross-coupling    1-[3-bromo-4-nitrophenyl)methyl]-4-methylpiperazine or a salt (e.g.,    HCl) thereof with methyl    5-amino-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate    or a salt thereof, particularly the HCl salt thereof:

-   in the presence of a palladium catalyst to prepare methyl    5-({5-[(4-methyl-1-piperazinyl)methyl]-2-nitrophenyl}amino)-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate    or a salt thereof, particularly the HCl salt thereof:

-   c) reducing methyl    5-({5-[(4-methyl-1-piperazinyl)methyl]-2-nitrophenyl}amino)-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate    or a salt (e.g., HCl) thereof to prepare methyl    5-({2-amino-5-[(4-methyl-1-piperazinyl)methyl]phenyl}amino)-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate    or a salt thereof, particularly the HCl salt thereof:

-   d) cyclizing methyl    5-({2-amino-5-[(4-methyl-1-piperazinyl)methyl]phenyl}amino)-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate    or a salt (e.g., HCl) thereof to prepare methyl    5-{6-[(4-methyl-1-piperazinyl)methyl]-1H-benzimidazol-1-yl}-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate    or a salt thereof, particularly the HCl salt thereof:

-    and-   e) reacting methyl    5-{6-[(4-methyl-1-piperazinyl)methyl]-1H-benzimidazol-1-yl}-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate    or a salt (e.g., HCl) thereof with formamide and a base (e.g.,    sodium methoxide) to prepare    5-{6-[(4-methylpiperazin-1-yl)methyl]-1H-benzimidazol-1-yl}-3-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxamide.

These and other embodiments and aspects of the invention are describedbelow in the Detailed Description and Examples which follow.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The term “alkyl” as used herein refers to linear or branched hydrocarbonchains having from 1 to 8 carbon atoms (i.e., C₁₋₈alkyl), unless adifferent number of atoms is specified. Examples of “alkyl” as usedherein include, but are not limited to, methyl, ethyl, n-propyl,n-butyl, n-pentyl, isobutyl, isopropyl and tert-butyl. Similarly, theterm “alkylene” refers to linear or branched divalent hydrocarbon chainscontaining from 1 to 8 carbon atoms, unless a different number of atomsis specified. Examples of “alkylene” as used herein include, but are notlimited to, methylene, ethylene, propylene, butylene and isobutylene.

As used herein, the term “alkenyl” refers to linear or branchedhydrocarbon chains having from 2 to 8 carbon atoms (i.e., C₂₋₈alkenyl),unless a different number of atoms is specified, and at least one and upto three carbon-carbon double bonds. Examples of “alkenyl” as usedherein include, but are not limited to ethenyl and propenyl.

The terms “halo” or “halogen” are synonymous and refer to fluoro,chloro, bromo and iodo unless otherwise stated.

As used herein, “haloalkyl” refers to an alkyl, as defined above,substituted by one or more halogen atoms, fluoro, chloro, bromo or iodo.Where the haloalkyl group may not have up to 8 carbon atoms, the numberof carbon atoms in the group is indicated as, for example,haloC₁₋₃alkyl. Examples of haloalkyl as used herein include, but are notlimited to fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl,trifluoroethyl and the like.

The term “oxo” as used herein refers to the group ═O attached directlyto a carbon atom of a hydrocarbon ring (e.g., cyclohexyl), or a C, N orS of a heterocyclic or heteroaryl ring to result in oxides, —N-oxides,sulfones and sulfoxides.

As used herein, the term “cycloalkyl” refers to a saturated monocycliccarbocyclic ring having from 3 to 8 carbon atoms, unless a differentnumber of atoms is specified. “Cycloalkyl” includes by way of examplecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl andcyclooctyl. Where indicated, the cycloalkyl may optionally besubstituted on any available carbon with one or more substituentsselected from the group consisting of halo, C₁₋₃alkyl, haloC₁₋₃alkyl(e.g., perfluoroalkyl), —OH, —O—C₁₋₃alkyl, —NH₂, —NH(C₁₋₃alkyl),—N(C₁₋₃alkyl)₂ and —CN. Particular cycloalkyl groups includeC₃₋₆cycloalkyl and substituted C₃₋₆cycloalkyl.

As used herein, the term “cycloalkenyl” refers to a non-aromaticmonocyclic carbocyclic ring having from 3 to 8 carbon atoms (unless adifferent number of atoms is specified) and up to 3 carbon-carbon doublebonds. “Cycloalkenyl” includes by way of example cyclobutenyl,cyclopentenyl and cyclohexenyl. “Cycloalkenyl” also includes substitutedcycloalkenyl. The cycloalkenyl may optionally be substituted on anyavailable carbon with one or more substituents selected from the groupconsisting of halo, C₁₋₃alkyl, haloC₁₋₃alkyl (e.g., perfluoroalkyl),—OH, —O—C₁₋₃alkyl, —NH₂, —NH(C₁₋₃alkyl), —N(C₁₋₃alkyl)₂ and —CN.

As used herein, the terms “heterocycle” and “heterocyclic” aresynonymous and refer to monocyclic saturated or unsaturated non-aromaticgroups having from 5 to 6 members (unless a different number of membersis specified) including 1, 2 or 3 heteroatoms selected from N, O and S,unless a different number of heteroatoms is specified. In allembodiments wherein the heterocycle includes 2 or more heteroatoms, theheteroatoms may be the same or different and are independently selectedfrom N, O and S. In all embodiments wherein the compound includes two ormore heterocyclic groups, the heterocyclic groups may be the same ordifferent and are independently selected. Examples of particularheterocyclic groups include but are not limited to tetrahydrofuran,dihydropyran, tetrahydropyran, pyran, thietane, 1,4-dioxane,1,3-dioxane, 1,3-dioxalane, piperidine, piperazine, pyrrolidine,morpholine, thiomorpholine, thiazolidine, oxazolidine,tetrahydrothiopyran, tetrahydrothiophene and the like.

As used herein, the term “N-heterocycle” refers to monocyclic saturatedor unsaturated non-aromatic groups having from 5 to 6 members (unless adifferent number of members is specified) including at least one N andoptionally 1 or 2 additional heteroatoms selected from N, O and S,unless a different number of additional heteroatoms is specified. TheN-heterocycle may be bound through the at least one N. By “additionalheteroatoms” is meant 1 or 2 heteroatoms in addition to the N alreadyspecified in the N-heterocycle ring. In all embodiments wherein theheterocycle includes 1 or more additional heteroatoms, the heteroatomsmay be the same or different and are independently selected from N, Oand S. In all embodiments wherein the compound of formula (I) includestwo or more N-heterocyclic groups, the N-heterocyclic groups may be thesame or different and are independently selected. Examples ofN-heterocycles include piperidine, piperazine, pyrrolidine, morpholineand thiomorpholine.

As used herein, the term “heteroaryl” refers to aromatic, monocyclicgroups having from 5 to 6 members (unless a different number of membersis specified) including 1, 2 or 3 heteroatoms selected from N, O and S,unless a different number of heteroatoms is specified. The N-heterocyclemay be bound through the at least one N. In all embodiments wherein theheteroaryl includes 2 or more heteroatoms, the heteroatoms may be thesame or different and are independently selected from N, O and S. In allembodiments wherein the compound includes two or more heteroaryl groups,the heteroaryl groups may be the same or different and are independentlyselected. Examples of particular heteroaryl groups include but are notlimited to furan, thiophene, pyrrole, imidazole, pyrazole, triazole,tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole,isothiazole, pyridine, pyridazine, pyrazine, pyrimidine,tetrahydropyrimidine and triazine.

As used herein, the term “N-heteroaryl” refers to aromatic, monocyclicgroups having from 5 to 10 members (unless a different number of membersis specified) including at least one N and optionally 1 or 2 additionalheteroatoms selected from N, O and S, unless a different number ofheteroatoms is specified. By “additional heteroatoms” is meant 1 or 2heteroatoms in addition to the N already present in the N-heteroaryl. Inall embodiments wherein the heteroaryl includes 1 or more additionalheteroatoms, the heteroatoms may be the same or different and areindependently selected from N, O and S. In all embodiments wherein thecompound includes two or more N-heteroaryl groups, the N-heteroarylgroups may be the same or different and are independently selected.Examples of N-heteroaryls include pyrrole, imidazole, pyrazole,thiazole, isoxazole, pyridine, pyridazine, pyrazine, pyrimidine andtriazine.

As used herein, the term “members” (and variants thereof e.g.,“membered”) in the context of heterocyclic and heteroaryl groups refersto the total number of ring atoms, including carbon and heteroatoms N, Oand/or S. Thus, an example of a 6-membered heterocyclic ring ispiperidine and an example of a 6-membered heteroaryl ring is pyridine.

As used herein, the term “optionally” means that the invention includesboth embodiments wherein the described condition is and is not met.Thus, an N-heterocycle optionally including 1 or 2 additionalheteroatoms describes N-heterocycles including no additional heteroatoms(i.e., only one N) as well as N-heterocycles including 1 or 2 additionalheteroatoms.

The present invention provides a new process for preparing compounds offormula (I):

-   -   wherein:    -   R¹ is OH, O-alkyl or NH₂;    -   R² is alkyl;    -   R³ is F, Cl, Br, alkyl or haloalkyl,    -   a is 0 or 1    -   R⁴ is selected from F, Cl, Br, alkyl, haloalkyl, alkenyl,        cycloalkyl, cycloalkenyl, phenyl, Het, —C(O)R⁷, —C(O)NR⁷R⁸,        —OR⁷, —O-phenyl, —O-benzyl, —O-Het, —O—R⁶-Het; —NR⁷R⁸,        —N(R⁷)C(O)R⁸, —N(R⁷)Het, —N(R⁷)S(O)₂R⁸, —N(R⁷)—R⁶—S(O)₂R⁸ and        —CN;        -   Het is selected from heterocycles and heteroaryls, wherein            said heterocycle or heteroaryl may optionally be substituted            with one or two substituents selected from halo, alkyl,            haloalkyl, oxo, OH, O-alkyl, alkylene-OH, and            alkylene-SO₂-alkyl;    -   R⁵ is selected from —NR⁷R⁸ and N-heterocycles, wherein said        N-heterocycle may optionally be substituted with one or two        substituents selected from halo, alkyl, haloalkyl, oxo, OH,        O-alkyl, alkylene-OH and alkylene-SO₂-alkyl;    -   R⁶ is alkylene; and    -   each R⁷ and R⁸ are the same or different and are each        independently selected from H and alkyl    -   and pharmaceutically acceptable salts thereof.

In one embodiment, the compounds of formula (I) are defined wherein R¹is NH₂.

In one embodiment, R² is methyl.

In one embodiment, R³ is halo or haloalkyl. In one particularembodiment, R³ is haloalkyl. In one preferred embodiment, R³ istrifluoromethyl.

In one embodiment, a is 0. It should be understood that when a is 0,there is no substituent R⁴.

In one embodiment wherein a is 1, R⁴ is selected from F, Cl, Br, alkyl,haloalkyl, cycloalkyl, phenyl, Het, —OR⁷, —O-phenyl, —O-benzyl, —O-Het,—O—R⁶-Het, —NR⁷R⁸, —N(R⁷)C(O)R⁸ and —N(R⁷)Het. In one particularembodiment, R⁴ is selected from F, Cl, Br, alkyl, haloalkyl, —OR⁷, and—NR⁷R⁸. In another particular embodiment, R⁴ is selected from phenyl,Het, —O-phenyl, —O-benzyl, —O-Het, —O—R⁶-Het and —N(R⁷)Het.

In one embodiment, Het in R⁴ (in each of the groups wherein that term isemployed, e.g., Het, —O-Het, etc.) is defined wherein Het is selectedfrom substituted and unsubstituted 5 and 6 membered N-heterocycles andN-heteroaryls, optionally having one additional heteroatom selected fromN, O and S, wherein said N-heterocycle or N-heteroaryl may optionally besubstituted with one or two substituents selected from alkyl, haloalkyl,oxo, OH and O-alkyl. In one embodiment, Het is selected from substitutedand unsubstituted 6 membered N-heterocycles optionally having oneadditional heteroatom selected from N, O and S, wherein saidN-heterocycle may optionally be substituted with one or two substituentsselected from alkyl and haloalkyl. In one embodiment, Het is selectedfrom substituted and unsubstituted 6 membered N-heterocycles optionallyhaving no additional heteroatoms, wherein said N-heterocycle mayoptionally be substituted with one or two substituents selected fromalkyl and haloalkyl.

In one embodiment, R⁵ is —NR⁷R⁸. In another embodiment, R⁵ is asubstituted or unsubstituted 5 or 6 membered N-heterocycle, optionallyhaving one additional heteroatom selected from N, O and S, wherein saidN-heterocycle may optionally be substituted with one or two substituentsselected from alkyl, haloalkyl, oxo, OH and O-alkyl. In a particularembodiment, R⁵ is a substituted or unsubstituted 6 memberedN-heterocycle, optionally having one additional heteroatom selected fromN, O and S, wherein said N-heterocycle may optionally be substitutedwith one or two substituents selected from alkyl and haloalkyl. In onepreferred embodiment, R⁵ is piperazine substituted with alkyl.

In one embodiment, R⁶ is C₁₋₃alkylene.

In one embodiment, each R⁷ and each R⁸ is the same or different and isindependently selected from H and C₁₋₃alkyl.

A preferred compound which may be prepared by the process of theinvention is5-{6-[(4-Methylpiperazin-1-yl)methyl]-1H-benzimidazol-1-yl}-3-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxamide.

The pharmaceutically acceptable salts of the compounds of formula (I)include conventional salts formed from pharmaceutically acceptableinorganic or organic acids or bases as well as quaternary ammoniumsalts. More specific examples of suitable acid salts includehydrochloric, hydrobromic, sulfuric, phosphoric, nitric, perchloric,fumaric, acetic, propionic, succinic, glycolic, formic, lactic, maleic,tartaric, citric, palmoic, malonic, hydroxymaleic, phenylacetic,glutamic, benzoic, salicylic, fumaric, toluenesulfonic, methanesulfonic(mesylate), naphthalene-2-sulfonic, benzenesulfonic hydroxynaphthoic,hydroiodic, malic, steroic, tannic and the like.

Other acids such as oxalic, while not in themselves pharmaceuticallyacceptable, may be useful in the preparation of salts useful asintermediates in obtaining the compounds of the invention and theirpharmaceutically acceptable salts. More specific examples of suitablebasic salts include sodium, lithium, potassium, magnesium, aluminium,calcium, zinc, N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine, N-methylglucamine and procaine salts.

A process according to the invention is depicted in the followingscheme.

-   -   wherein all variables are as defined above.

Generally, the process comprises the steps of:

-   a) reacting a compound of formula (II) with an amine of formula H—R⁵    to prepare a compound of formula (III) or a salt thereof;-   b) cross-coupling the compound of formula (III) or a salt thereof    with a compound of formula (IV) or a salt thereof to prepare a    compound of formula (V) or a salt thereof;-   c) reducing a compound of formula (V) or a salt thereof to prepare a    compound of formula (VI) or a salt thereof; and-   d) cyclizing the compound of formula (VI) or a salt thereof to    prepare a compound of formula (I-A) or a salt thereof.

Optionally, the process may further comprise the step of converting theester compound of formula (I-A) or a salt thereof to a correspondingamide compound of formula (I-B). The process may further comprise thestep of converting the ester compound of formula (I-A) or salt thereofto the acid compound of formula (I-C) or salt thereof.

More particularly, compounds of formula (III) or a salt thereof may beprepared by reacting a compound of formula (II) with an amine of formulaH—R⁵. The reaction may be carried out using reductive aminationtechniques. Typically, the amine and the compound of formula (II) arereacted in the presence of an acid and a reducing agent in a suitablesolvent. Conveniently, the reaction may be carried out at roomtemperature. Suitable solvents for this reaction include but are notlimited to toluene, dichloromethane, dichloroethane benzene andtetrahydrofuran. The acid may, for example, be acetic acid. Examples ofsuitable reducing agents for this reaction include but are not limitedto sodium triacetoxyborohydride and sodium cyanoborohydride. Compoundsof formula (II) are commercially available or may be prepared usingconventional techniques known in the art. In one embodiment, this stepof reacting the compound of formula (II) with the amine prepares the HClsalt of the compound of formula (III) through the use of HCl acid in theisolation of the product. The HCl salt may be the mono or bis HCl salt.In a particular embodiment, the HCl salt is the bis HCl, bis hydrate ofthe compound of formula (III).

Reaction of a compound of formula (III) or a salt thereof (e.g., HCl,particularly bis HCl bis hydrate) with a compound of formula (IV) or asalt (e.g., HCl) thereof, may be carried out using conventionalcross-coupling techniques. The choice of reagents for the cross-couplingreaction will depend upon the definition of Hal in formula (III). Inthose embodiments wherein Hal is fluoride (F), the cross-couplingreaction is carried out in the presence of a base. Examples of suitablebases for this reaction include, but are not limited to potassiumhydroxide and lithium hydroxide. Suitable solvents for this reactioninclude but are not limited to acetonitrile, n-butyl acetate andisopropyl acetate. The reaction may be carried out at room temperatureor at elevated temperatures. In those embodiments wherein Hal ischloride (Cl), bromide (Br) or iodide (I), the reaction may be carriedout by using transition metal catalyzed cross-coupling techniquesconventional in the art of organic synthesis. Palladium catalyzedcross-coupling conditions are preferred. Palladium catalyzedcross-coupling conditions include but are not limited to reacting thecompound of formula (III) or salt thereof with the compound of formula(IV) or salt thereof in the presence of a palladium source, a suitableligand, and a base in a suitable inert solvent. Examples of suitablepalladium sources include but are not limited totris(dibenzylideneacetone)dipalladium(0), palladium(II) acetate andtetrakis(triphenylphosphine)palladium(0). Examples of suitable ligandsinclude but are not limited to phosphine ligands such as2-(di-t-butylphosphino)biphenyl and2,2′-bis(diphenylphosphino)-1,1′-binaphthyl,2-dicyclohexylphosphio-2′,4′,6′-triisopropylbiphenyl which iscommercially available from Sigma-Aldrich under the name “X-Phos”(catalog no. 63,806-4) and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, which is commerciallyavailable under the name “XANTPHOS” from Sigma-Aldrich. In oneembodiment where Hal is Cl, the ligand is X-Phos. In one embodimentwherein Hal is Br, the ligand is XANTPHOS. Examples of suitable basesinclude but are not limited to cesium carbonate, potassium carbonate andpotassium phosphate. Examples of suitable inert solvents include but arenot limited to toluene, tetrahydrofuran, N,N-dimethylformamide and1,4-dioxane. The reaction may be carried out at room temperature orelevated temperature depending upon the catalyst selected. See, Yang, B.H.; Buchwald, S. L. Journal of Organometallic Chemistry 1999, 576,125-146. The reaction may be initiated at elevated temperatures and thenmay be cooled to room temperature.

In one embodiment, the compound of formula (III) is defined wherein Halis F, Cl or Br. Compounds of formula (IV) and salts thereof are known inthe art and may be prepared using conventional methods such as thosedescribed in PCT Publication Nos. WO2007/036061 and WO2007/030359, bothto SmithKline Beecham Corp. For example, one process for preparingcompounds of formula (IV) is depicted in the following Scheme.

-   -   wherein:    -   PPh3 is triphenyl phosphine;    -   DTAD is di-tert-butylazodicaroxylate;    -   THF is tetrahydrofuran;    -   TBME is tert-butylmethylether    -   (dichloromethane may also be used as the solvent);    -   and all variables are as defined above.

The reaction of the compound of formula (III) or salt (e.g., HCl,particularly bis HCl bis hydrate) thereof with a compound of formula(IV) or salt (e.g., HCl) thereof prepares a compound of formula (V) orsalt thereof, particularly HCl salt thereof, and more particularly bisHCl salt thereof.

The reduction of the compound of formula (V) or salt (e.g., HCl)thereof, specifically, the nitro functionality of the compound offormula (V) to the corresponding aniline compound of formula (VI) orsalt thereof, particularly the HCl salt thereof, may be carried outusing conventional reduction or hydrogenation techniques suitable forsuch compounds. In particular, the reduction may be effected usingconditions such as palladium on carbon under a hydrogen atmosphere. Thereaction may be carried out neat or in a solvent at elevated pressure.Suitable solvents include but are not limited to toluene, water,ethanol, methanol, ethyl acetate, THF, dioxane, and mixtures of any ofthe foregoing. Other suitable reduction techniques include palladiumwith ammonium formate, tin(II)chloride, platinum on carbon withhydrogen, platinum oxide with hydrogen, nickel with hydrogen, iron withacetic acid, aluminum with ammonium chloride, borane and sodiumdithionite. The reaction may optionally be heated to between about 50and about 120° C.

The cyclization of compounds of formula (VI) or a salt (e.g., HCl)thereof, may be carried out using a suitable cyclizing agent. Suitablecyclizing agents will be apparent to those skilled in the art of organicsynthesis and include, for example triethylorthoformate ortrimethylorthoformate or formic acid, optionally in the presence of anacid catalyst, such as for example, hydrochloric acid or formic acid orpyridinium p-toluenesulfonate. In one preferred embodiment, thecyclizing agent is trimethylorthoformate. Conveniently, the reaction ofa compound of formula (VI) or a salt (e.g., HCl) thereof with thecyclization agent may be carried out neat, at room temperature or atelevated temperatures. The cyclization reaction prepares a compound offormula (I-A) or a salt thereof. In one embodiment, the cyclization ofthe compound of formula (VI) or salt thereof prepares a HCl salt of thecompound of formula (I-A). In a particular embodiment, the compound offormula (I-A) is in the form of a tris HCl salt thereof.

In another embodiment, the process of preparing a compound of formula(I-A) or a salt (e.g., HCl, particularly tris HCl) thereof may beconveniently carried out by performing a one-pot reduction-cyclizationprocedure on a compound of formula (V) or salt (e.g., HCl) thereof usingconditions such as palladium on carbon under a hydrogen atmosphere inthe presence of trimethylorthoformate and excess acid catalyst. In thisembodiment, trimethylorthoformate may be used as a solvent or aco-solvent with another suitable inert solvent, such as methanol.

The compound of formula (I-A) or salt (e.g., HCl, particularly tris HCl)thereof may be converted to the corresponding amide compound of formula(I-B) or acid compound of formula (I-C).

-   -   wherein all variables are as defined above.

One process for preparing a compound of formula (I-B) comprises reactingthe compound of formula (I-A) or salt (e.g., HCl, particularly tris HCl)with excess ammonia. Typically, the reaction is carried out by heatingthe reaction in a sealed vessel with an excess of ammonia at temperatureof from about 50° C. to about 120° C. Suitable solvents for thisreaction include but are not limited to methanol, ethanol, isopropanol,tetrahydrofuran, and dioxane.

Alternatively, the amide may be prepared by reacting the correspondingester with formamide and a base. The reaction is typically carried outin a solvent or mixture of solvents such as tetrahydrofuran and toluene.Conveniently, the reaction may be carried out at room temperature.Preferably, the base is sodium methoxide.

A compound of formula (I-C) may be prepared by a process comprisinghydrolyzing the compound of formula (I-A). The hydrolysis step may becarried out using conventional hydrolysis techniques well known to thoseskilled in the art.

A compound of formula (I-B) may be prepared from a compound of formula(I-C) by reacting with ammonia using conventional amide bond couplingconditions, although the foregoing method for preparing the amide offormula (I-B) from the ester for formula (I-A) is preferred. Thereaction of the acid to the amide may be carried out in an inert solventusing a variety of commercially available coupling reagents. Thecarboxylic acid compound of formula (I-C) may optionally be convertedinto the corresponding acid chloride and subsequently treated withammonia to prepare the corresponding amide. Suitable reagents for thereaction of such acid chlorides include but are not limited to oxalylchloride, thionyl chloride, and1-chloro-N,N,2-trimethyl-1-propenylamine. Base may be optionally addedto the coupling reaction. The reaction may optionally require heating toa temperature of from about 40° C. to about 100° C. Suitable basesinclude but are not limited to trialkylamines, pyridine, and4-(dimethylamino)pyridine. Examples of suitable solvents for thisreaction include but are not limited to dichloromethane, chloroform,benzene, toluene, N,N-dimethylformamide and dichloroethane.

Additional transformations for converting a particular compound offormula (I) into a different compound of formula (I) are described inPCT Publication No. WO04/014899.

Within the scope of compounds of formula (I) are compounds of formula(X):

-   -   wherein:    -   R³ is F, Cl, Br, alkyl or haloalkyl;    -   R¹⁰ is H or alkyl.

In one particular embodiment, the present invention provides a processfor preparing compound of formula (X) comprising the steps of:

-   a) reacting 3-bromo-5-nitrobenzaldehyde:

-   with an amine of formula:

-   to prepare a compound of formula (III-a) or a salt thereof,    particularly a HCl salt (more particularly bis HCl bis hydrate salt)    thereof:

-   b) cross-coupling the compound of formula (III-a) or salt (e.g.,    HCl, particularly bis HCl bis hydrate) with a compound of formula    (IV-a) or salt (e.g., HCl) thereof:

-   in the presence of a palladium catalyst to prepare a compound of    formula (V-a) or a salt thereof, particularly HCl salt thereof, more    particularly bis HCl salt thereof:

-   c) reducing the compound of formula (V-a) or salt thereof (e.g.,    HCl, particularly bis HCl) to prepare a compound of formula (VI-a)    or salt thereof, particularly a HCl salt thereof:

-   d) cyclizing the compound of formula (VI-a) or salt (e.g., HCl)    thereof in the presence of an orthoester and an acid catalyst to    prepare a compound of formula (IX) or a salt thereof, particularly a    HCl salt thereof, more particularly a tris HCl salt thereof:

-    and    -   e) converting the ester compound of formula (IX) or salt (e.g.,        HCl, particularly tris HCl salt) thereof to the corresponding        amide compound of formula (X).

According to this embodiment, step a) of reacting3-bromo-5-nitrobenzaldehyde with the indicated amine is carried out atroom temperature in the presence of acetic acid and sodiumtriacetoxyborohydride in toluene to prepare a compound of formula(III-a) or salt (e.g., HCl, particularly bis HCl bis hydrate) thereof.

Step b) of cross-coupling the compound of formula (III-a) or salt (e.g.,HCl, particularly bis HCl bis hydrate) thereof with a compound offormula (IV-a) or salt thereof is typically carried out usingconventional palladium catalyzed cross-coupling conditions. Preferredcross-coupling conditions for the preparation of compounds of formula(V-a) or salts there include but are not limited to reacting thecompound of formula (III-a) or salt thereof with the compound of formula(IV-a) or salt thereof in the presence oftris(dibenzylideneacetone)-dipalladium(0), XANTPHOS and cesiumcarbonate. The reaction may be initiated at elevated temperature ofabout 50° C. to about 75° C. and then cooled to room temperature. In oneembodiment, the compound of formula (V-a) prepared by this method is inthe form of the HCl salt, more particularly the bis HCl salt.

According to this embodiment, the reduction of the compound of formula(V-a) or salt (e.g., HCl, particularly bis HCl) thereof to thecorresponding aniline compound of formula (VI-a) or salt thereof iscarried out using palladium on carbon under a hydrogen atmosphere. Thecyclization of the compound of formula (VI-a) or salt thereof is thencarried out using trimethylorthoformate in the presence of hydrochloricacid. In one preferred embodiment, the reduction and cyclizationreactions are carried out in a one-pot reaction, without isolation ofthe aniline of formula (VI-a) or salt thereof. In one embodiment, thecompound of formula (VI-a) prepared by this method is in the form of theHCl salt.

The cyclization of a compound of formula (VI-a) or a salt (e.g., HCl)thereof, to prepare a compound of formula (IX) or salt thereof may becarried out using the methods described above for the cyclization of acompound of formula (VI) or salt thereof to prepare the ester compoundof formula (I-A). According to this embodiment the cyclization agent ispreferably trimethylorthoformate. The cyclization reaction prepares acompound of formula (IX) or a salt thereof. In one embodiment, thecyclization of the compound of formula (VI-a) or salt (e.g., HCl)thereof prepares a HCl salt of the compound of formula (IX). In aparticular embodiment, the compound of formula (IX) is in the form of atris HCl salt thereof.

In another embodiment, the process of preparing a compound of formula(IX) or a salt (e.g., HCl, particularly tris HCl) thereof may beconveniently carried out by performing a one-pot reduction-cyclizationprocedure on a compound of formula (V-a) or salt (e.g., HCl) thereofaccording to the method described above for the one-pot reductioncyclization procedure using a compound of formula (V).

In one embodiment, step e) of converting the ester compound of formula(IX) or salt (e.g., HCl, particularly tris HCl) thereof to thecorresponding amide compound of formula (X) is carried out by reactingwith formamide and a base. In one preferred embodiment, the base issodium methoxide.

In one preferred embodiment, the present invention provides a processfor preparing5-{6-[(4-Methylpiperazin-1-yl)methyl]-1H-benzimidazol-1-yl}-3-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxamide:

The process comprises the steps of:

-   a) reacting 3-bromo-5-nitrobenzaldehyde:

-   with N-methyl piperazine:

-   to prepare 1-[3-bromo-4-nitrophenyl)methyl]-4-methylpiperazine or a    salt thereof, particularly a HCl salt (more particularly bis HCl bis    hydrate salt) thereof:

-   b) cross-coupling    1-[3-bromo-4-nitrophenyl)methyl]-4-methylpiperazine (or salt (e.g.,    HCl, particularly bis HCl) thereof) with methyl    5-amino-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate    or a salt (e.g., HCl) thereof:

-   in the presence of a palladium catalyst (preferably    tris(dibenzylideneacetone)-dipalladium(0)) to prepare methyl    5-({5-[(4-methyl-1-piperazinyl)methyl]-2-nitrophenyl}amino)-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate    or salt thereof, particularly HCl salt thereof, more particularly    bis HCl salt thereof:

-   c) reducing methyl methyl    5-({5-[(4-methyl-1-piperazinyl)methyl]-2-nitrophenyl}amino)-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate    (or salt (e.g., HCl, particularly bis HCl) thereof) to prepare    methyl    5-({2-amino-5-[(4-methyl-1-piperazinyl)methyl]phenyl}amino)-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate    or salt thereof, particularly HCl salt thereof:

-   d) cyclizing methyl    5-({2-amino-5-[(4-methyl-1-piperazinyl)methyl]phenyl}amino)-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate    or a salt (e.g., HCl) thereof to prepare methyl    5-{6-[(4-methyl-1-piperazinyl)methyl]-1H-benzimidazol-1-yl}-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate    or salt thereof, particularly HCl salt thereof, more particularly    tris HCl salt thereof:

-    and-   e) reacting methyl    5-{6-[(4-methyl-1-piperazinyl)methyl]-1H-benzimidazol-1-yl}-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate    or a salt thereof (e.g., HCl, more particularly tris HCl) with    formamide and a base, particularly sodium methoxide to prepare    5-{6-[(4-methylpiperazin-1-yl)methyl]-1H-benzimidazol-1-yl}-3-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxamide.

In one embodiment, steps c) of reducing and d) of cyclizing are combinedas a one-pot reaction using palladium on carbon in a hydrogenatmosphere, trimethylorthoformate and excess hydrochloric acid.

The process of the present invention provides certain advantages overpreviously disclosed processes for preparing compounds of formula (I)for example, improved convergency and reduced number of chemical steps.The process of the present invention is suitable for the large scaleproduction of commercial quantities of the compounds for use in thetreatment of humans. The process of the present invention also enablesthe isolation of a number of intermediates through crystallizationand/or salt-forming steps which in turn enables purification at varioussteps of the process.

Examples

The following examples are intended for illustration only and are notintended to limit the scope of the invention in any way, the inventionbeing defined by the claims which follow.

The following abbreviations, as employed in the examples, have therecited meanings.

g gram(s) mg milligram(s) mol mole(s) mmol millimole(s) mL milliliter(s)h hour(s) min minute(s) ° C. degrees Centigrade HPLC High PerformanceLiquid Chromatography Cs₂CO₃ cesium carbonate DCM dichloromethane EtOAcethyl acetate H₂ hydrogen H₂O water HCl hydrochloric acid K₂CO₃potassium carbonate KOH potassium hydroxide MeOH methanol N₂ nitrogenNa₂SO₄ sodium sulfate NaHCO₃ sodium bicarbonate NEt₃ triethylamine Pd/Cpalladium on carbon THF tetrahydrofuran

Reagents are commercially available or are prepared according toprocedures in the literature.

1-[(3-Bromo-4-nitrophenyl)methyl]-4-methylpiperazine

N-methyl piperazine (0.95 mL, 8.56 mmol) was added dropwise to asuspension of 3-bromo-4-nitrobenzaldehyde (0.985 g, 4.28 mmol) andacetic acid (0.29 mL, 5.14 mmol) in toluene (5.5 mL) at roomtemperature. The reaction mixture was stirred for 1 h at roomtemperature before the addition of sodium triacetoxyborohydride (1.36 g,6.42 mmol). The reaction mixture was stirred for 2 h. Further toluene(2.1 mL) and sodium triacetoxyborohydride (0.18 g, 0.86 mmol) was addedand the reaction mixture was stirred for 2 hours and then quenched bythe addition of MeOH (0.99 mL). The reaction mixture was stirred for 30min, saturated aqueous NaHCO₃ (6.01 mL) was then added and the reactionmixture was stirred overnight. The phases were separated and the aqueouslayer was extracted with toluene (4.0 mL). The combined organic extractswere concentrated under reduced pressure and purified by flash columnchromatography (EtOAc:MeOH:NEt₃ 9:1:0.1) to give the title compound(1.18 g, 88%) as a low melting point waxy brown solid.

δ_(H) (400 MHz, CDCl₃) 7.81 (1H, d, J 8.3, Ar H), 7.74 (1H, d, J 1.5, ArH), 7.42 (1H, dd, J 1.7, 8.3, Ar H), 3.53 (2H, s, NCH₂Ar), 2.49 (8H, brs, 2×NCH₂CH₂), 2.31 (3H, s, NCH₃).

1-[(3-Bromo-4-nitrophenyl)methyl]-4-methylpiperazine dihydrochloridedihydrate

N-methyl piperazine (24.1 mL, 217 mmol) was added dropwise to a solutionof 3-bromo-4-nitrobenzaldehyde (50.0 g, 217 mmol) and acetic acid (6.2mL, 12 mmol) in THF (250 mL) at room temperature. The reaction mixturewas stirred for 2 h at room temperature and then cooled to 15° C. Sodiumtriacetoxyborohydride (69 g, 326 mmol) was added in 6 equal portions,maintaining the internal temperature at 15±5° C. The reaction mixturewas stirred for a further 2 hours, allowing warming to room temperature.The reaction was quenched by the dropwise addition of MeOH (50 mL).Aqueous sodium hydroxide (3.75 M, 250 mL) was added and the mixture wasstirred at room temperature for 45 mins, then the layers separated. Theaqueous phase was discarded. The organic phase was acidified withaqueous hydrochloric acid (5 M, 125 mL) and diluted with water (250 mL)and EtOAc (250 mL). The mixture was stirred vigorously for 10 minutes,then the layers were allowed to separate. The organic phase wasdiscarded. The aqueous phase was made basic with aqueous K₂CO₃ (25% w/v,300 mL) and then extracted with EtOAc (250 mL). The organic extract washeated to 45° C. Water (18 mL) was added, followed by the dropwiseaddition of HCl (4 M in dioxane, 109 mL) over 1 hour. The resultingslurry was aged for a further hour, cooled to room temperature,filtered, washing with EtOAc (175 mL) and dried under reduced pressureto give the title compound (75.0 g, 82% th) as a yellow crystallinesolid.

δ_(H) (400 MHz, D₂O) 8.02-7.99 (2H, m, Ar CH), 7.68 (1H, d, J 0.0, ArCH), 4.47 (2H, s, NCH₂Ar), 3.60 (8H, br s, N(CH₂CH₂)₂), 2.99 (3H, s,NCH₃); LRMS found m/z [ES⁺] 314 and 316, [C₁₂H₁₆ ⁷⁹BrN₃O₂+H]⁺ requires314, [C₁₂H₁₆ ⁸¹BrN₃O₂+H]⁺ requires 316.

1-[(3-fluoro-4-nitrophenyl)methyl]-4-methylpiperazine

N-methyl piperazine (1.97 mL, 17.8 mmol) was added dropwise to asolution of 3-fluoro-4-nitrobenzaldehyde (1.50 g, 8.88 mmol) and aceticacid (0.20 mL, 3.54 mmol) in toluene (8.4 mL) at room temperature. Thereaction mixture was stirred for 1.5 h at room temperature before theaddition of further toluene (3.15 mL) and sodium triacetoxyborohydride(2.97 g, 14.0 mmol). The reaction mixture was stirred for 70 min andthen further sodium triacetoxyborohydride (0.40 g, 1.9 mmol) was added.The reaction mixture was stirred for 50 min, and then quenched by theaddition of MeOH (2 mL) and saturated aqueous NaHCO₃ (10 mL). Thereaction mixture was stirred for 30 min. The phases were separated andthe aqueous layer was extracted with toluene (2×20 mL, 1×10 mL). Thecombined organic extracts were concentrated under reduced pressure andpurified by flash column chromatography (EtOAc:MeOH:NEt₃ 19:1:0.1) togive the title compound (1.85 g, 82%) as an orange oil.

δ_(H) (400 MHz, CDCl₃) 8.02 (1H, t, J 8.1, Ar H), 7.34 (1H, d, J 11.9,Ar H), 7.26 (1H, d, J 8.6, Ar H), 3.57 (2H, s, NCH₂Ar), 2.49 (8H, br s,2×NCH₂CH₂), 2.31 (3H, s, NCH₃); LRMS found m/z [ES⁺] 254.

1-[(3-chloro-4-nitrophenyl)methyl]-4-methylpiperazine

N-methyl piperazine (2.50 mL, 22.5 mmol) was added dropwise to asolution of 3-chloro-4-nitrobenzaldehyde (2.09 g, 11.3 mmol) and aceticacid (0.29 mL, 5.14 mmol) in toluene (11.7 mL) at room temperature. Thereaction mixture was stirred for 1.5 h at room temperature before theaddition of further toluene (4.4 mL) and sodium triacetoxyborohydride(3.58 g, 16.9 mmol). The reaction mixture was stirred at roomtemperature overnight and then quenched by the addition of MeOH (3 mL)and saturated aqueous NaHCO₃ (23 mL). The reaction mixture was stirredfor 30 min. The phases were separated and the aqueous layer wasextracted with toluene (2×30 mL). The combined organic extracts wereconcentrated under reduced pressure and purified by flash columnchromatography (EtOAc:MeOH:NEt₃ 9:1:0.1) to give the title compound(2.17 g, 71%) as an orange oil.

δ_(H) (400 MHz, CDCl₃) 7.84 (1H, t, J 8.3, Ar H), 7.56 (1H, d, J 1.5, ArH), 7.38 (1H, dd, J 8.3, 1.5, Ar H), 3.54 (2H, s, NCH₂Ar), 2.48 (8H, brs, 2×NCH₂CH₂), 2.30 (3H, s, NCH₃).

Methyl5-({5-[(4-methyl-1-piperazinyl)methyl]-2-nitrophenyl}amino)-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate

A mixture of 1-[(3-bromo-4-nitrophenyl)methyl]-4-methylpiperazine (0.675g, 2.15 mmol), methyl5-amino-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate(0.794 g, 2.30 mmol), Cs₂CO₃ (3.50 g, 10.7 mmol), XANTPHOS (0.053 g,0.088 mmol) and tris(benzylideneacetone)dipalladium(0) (0.039 g, 0.043mmol) in dioxane (5.4 mL) was heated to 55° C. for 1.5 h, analysed byHPLC, then cooled to room temperature. Heptane (2.4 mL), charcoal (0.27g) and celite (0.27 g) were added. The suspension was stirred for 30 minat room temperature, and then filtered over celite, rinsing with toluene(13.5 mL×3). The filtrate was concentrated under reduced pressure andpurified by flash column chromatography (DCM:MeOH:NEt₃ 9:1:0.1) to givethe title compound (0.867 g, 70%) as a red amorphous solid.

δ_(H) (400 MHz, CDCl₃) 9.72 (1H, s, NH), 8.14 (1H, d, J 8.8, Ar H), 7.93(1H, d, J 8.8, Ar H), 7.67-7.57 (2H, m, Ar H), 7.44-7.35 (2H, m, Ar H),6.92 (1H, dd, J 8.8, 1.2, Ar H), 6.43 (1H, s, SC═CH), 5.73 (1H, q, J6.4, CH₃CHO), 3.88 (3H, s, OCH₃), 3.47 and 3.41 (2×1H d, J 14.5,NCH₂Ar), 2.48 (8H, br s, 2×NCH₂CH₂), 2.30 (3H, s, NCH₃), 1.72 (3H, d, J6.4, CH₃CHO); LRMS found m/z [ES⁻] 577.

Alternatively, methyl5-({5-[(4-methyl-1-piperazinyl)methyl]-2-nitrophenyl}amino)-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylatemay be prepared by either of the following methods:

A mixture of 1-[(3-chloro-4-nitrophenyl)methyl]-4-methylpiperazine(0.313 g, 1.16 mmol), methyl5-amino-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate(0.401 g, 1.16 mmol), K₂CO₃ (0.401 g, 2.90 mmol), X-Phos (0.0587 g, 0.12mmol), tris(benzylideneacetone)dipalladium(0) (0.0531 g, 0.06 mmol) andtert-butanol (4.6 mL) in a sealed tube was heated at 80° C. for 18 h.The crude reaction mixture was filtered through celite, washing withtoluene and then purified by flash column chromatography(EtOAc:MeOH:NEt₃) to give the title compound (0.534 g, 70%) as a redamorphous solid.

A solution of 1-[(3-fluoro-4-nitrophenyl)methyl]-4-methylpiperazine(0.733 g, 2.90 mmol) in acetonitrile (5 mL) was added dropwise to amixture of methyl5-amino-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate(1.00 g, 2.90 mmol) and KOH (0.325 g, 5.79 mmol) in acetonitrile (10 mL)at 0° C. The reaction mixture was allowed to warm to room temperatureovernight and then heated to 40° C. for 1 h until analysis by HPLCshowed complete consumption of starting materials. The reaction mixturewas partitioned between EtOAc (50 mL) and H₂O (50 mL). The organic layerwas washed with saturated aqueous NaHCO₃ (10 mL), concentrated underreduced pressure and then purified by flash column chromatography(DCM:MeOH 98:2 to 85:15, then EtOAC:MeOH 99:1 to 85:15) to give thetitle compound (0.85 g, 50%) as a red amorphous solid.

Methyl5-({5-[(4-methyl-1-piperazinyl)methyl]-2-nitrophenyl}amino)-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylatedihydrochloride

K₂CO₃ (100 g) was dissolved in water (225 mL) and the resulting solutionwas cooled to 25-30° C.1-[(3-bromo-4-nitrophenyl)methyl]-4-methylpiperazine dihydrochloride(50.0 g), methyl5-amino-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylatehydrochloride (53.7 g) and 2-methyl THF (250 mL) were added and themixture was stirred until complete dissolution had taken place. Thelayers were separated, retaining the organic phase. 2-Methyltetrahydrofuran (40 mL) was added and the mixture was distilled underreduced pressure to a volume of 350-400 mL. Xantphos (2.32 g, 3 mol %)was added, followed by cesium carbonate (48.0 g) andtris(benzylideneacetone)dipalladium(0) (1.84 g, 1.5 mol %). The reactionmixture was heated to 70-75° C. until judged complete by HPLC and thencooled to 20° C. Water (250 mL) was added and the mixture stirred todissolve the inorganics. The mixture was filtered through celite, thenthe phases allowed to separate. The aqueous phase was discarded. Thecelite was washed with MeOH (200 mL). The MeOH wash was added to theprevious organic phase. The mixture was slowly added to 5 M aqueous HClover approximately 40 minutes. The resulting crystalline slurry wasstirred overnight at room temperature, then filtered, washing with MeOH(100 mL, cooled to 0° C.) and dried under reduced pressure to give thetitle compound (72.8 g, 87% th) as orange to red crystalline sold.

δ_(H) (500 MHz, CDCl₃) 13.67 (1H, s, HCl), 9.50 (1H, s, NH) 8.27 (1H, d,J 8.5, Ar CH), 7.92 (1H, d, J 8.0, Ar CH), 7.60-7.66 (2H, m, 2×Ar CH),7.54 (1H, d, J 1.5, Ar CH), 7.41-7.47 (2H, m, Ar CH), 6.59 (1H, s,SCCH), 5.83 (1H, q, J 6.5, OCHCH₃), 4.21 (2H, 2×d, J 13.0, NCH₂Ar), 4.07(2H, s, NCH₂CH₂), 3.90-3.97 (2H, m, NCH₂CH₂), 3.87 (3H, s, OCH₃), 3.51(2H, d, J 13.0, NCH₂CH₂), 3.44 (2H, t, J 10.5, NCH₂CH₂), 2.89 (3H, s,NCH₃), 1.72 (d, J 6.0, OCHCH₃); LRMS found m/z [ES⁺] 579,[C₂₇H₂₉F₃N₄O₅S+H]⁺ requires 579.

Methyl5-({2-amino-5-[(4-methyl-1-piperazinyl)methyl]phenyl}amino)-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate

A mixture of methyl5-({5-[(4-methyl-1-piperazinyl)methyl]-2-nitrophenyl}amino)-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate(0.24 g, 0.415 mmol), 5% Pd/C (0.144 g), HCl (1.25 M in MeOH, 0.034 mL,0.043 mmol), trimethylorthoformate (1.66 mL, 15.2 mmol) in toluene (0.58mL) was hydrogenated under a H₂ atmosphere at 1.1 bar pressureovernight. The vessel was purged with N₂ and the reaction mixture wasanalysed by HPLC to confirm presence of the title compound which was notpurified, but used crude in the next step. LRMS found m/z [ES⁺] 549.

Methyl5-{6-[(4-methyl-1-piperazinyl)methyl]-1H-benzimidazol-1-yl}-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate

HCl (1.25 M in MeOH, 1.00 mL, 1.25 mmol) was added to a crude solutionof methyl5-({2-amino-5-[(4-methyl-1-piperazinyl)methyl]phenyl}amino)-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylatefrom the previous step (2.5 mL). The reaction mixture was stirred for 10min and then filtered through celite, washing with toluene (30 mL). Thefiltrate was concentrated under reduced pressure and partitioned betweenEtOAc (15 mL) and saturated aqueous Na₂CO₃ (15 mL) and then purified byflash column chromatography (EtOAc:MeOH:NEt₃ 9:1:0.1) to give the titlecompound (0.175 g, 75%) as a pale yellow amorphous solid.

δ_(H) (400 MHz, CDCl₃) 7.96-7.88 (2H, m, Ar H), 7.74 (1H, d, J 8.3, ArH), 7.70-7.58 (2H, m, Ar H), 7.46-7.32 (3H, m, Ar H), 6.76 (1H, s,SC═CH), 5.83 (1H, q, J 6.1, CH₃CHO), 3.93 (3H, s, OCH₃), 3.62 and 3.58(2×1H d, J 13.0, NCH₂Ar), 2.50 (8H, br s, 2×NCH₂CH₂), 2.31 (3H, s,NCH₃), 1.78 (3H, d, J 6.1, CH₃CHO); LRMS found m/z [ES⁺] 559.

Methyl5-{6-[(4-methyl-1-piperazinyl)methyl]-1H-benzimidazol-1-yl}-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylatetrihydrochloride

Methyl5-({5-[(4-methyl-1-piperazinyl)methyl]-2-nitrophenyl}amino)-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylatedihydrochloride (50.0 g, 76.8 mmol) was suspended in MeOH (100 mL) andtrimethylorthoformate (200 mL) and stirred for half an hour. Ammoniumformate (30.0 g) and 10% Pd/C (25 g, 15.4 mol %) were added and themixture was heated to 35° C. The temperature was increased to 60° C.over 6 hours and then held at 60° C. overnight before filtering throughfibreglass paper, washing with EtOAc (300 mL). The filtrate was washedwith aqueous sodium hydroxide (2 M, 250 mL) and then brine (2×150 mL). Asolution of HCl (4 M) was prepared by dropwise addition of acetylchloride (16.4 mL) to MeOH (41.3 mL), cooled with an ice-bath. Thissolution was warmed to room temperature and then added dropwise overhalf an hour to the reaction mixture at 45° C. The mixture was stirredfor a further half an hour at 45° C., cooled to room temperature over 1hour and then cooled in an ice-bath for a further hour, filtered,washing with EtOAc (150 mL) and then dried under reduced pressure togive the title compound (42.7 g, 83% th) as off-white crystalline solid.

δ_(H) (400 MHz, D₂O) 8.63 (1H, s, NCHN), 7.87-7.84, 7.70-7.56 and7.47-7.42 (7H, 4×m, Ar CH), 7.05 (1H, s, SCCH), 5.90 (1H, q, J 4.0,OCHCH₃), 4.49 (2H, 2×d, J 13.5, NCH₂), 3.90 (3H, s, OCH₃), 3.58 (8H, brs, N(CH₂CH₂)₂), 3.00 (3H, s, NCH₃), 1.70 (3H, d, J 5.5, CH₃CHO); LRMSfound m/z [ES⁺] 559, [C₂₈H₂₉F₃N₄O₃S+H]⁺ requires 559.

5-{6-[(4-Methylpiperazin-1-yl)methyl]-1H-benzimidazol-1-yl}-3-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxamide

Formamide (1.08 mL, 26.5 mmol) followed by 25% w/w sodium methoxide inMeOH (1.82 mL, 7.6 mmol) are added to a solution of methyl5-{6-[(4-methyl-1-piperazinyl)methyl]-1H-benzimidazol-1-yl}-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate(5.0 g, 8.95 mmol) in THF (50 mL) and toluene (10 mL) at roomtemperature. The reaction mixture is heated at ca 65° C. for about 18 hand then cooled to ca 30° C. The reaction mixture is diluted with EtOAc(25 mL) and H₂O (25 mL) and then the biphasic mixture is separated. Theorganic phase is washed sequentially with H₂O (25 ml), saturated aqueousNa₂CO₃ and finally H₂O (2×25 mL). The organic phase is then concentratedby rotary evaporation and the concentrate diluted with EtOAc (30 mL) andthen heated at ca 70° C. for about 1 h. The resulting suspension is thencooled to about 20° C. and stirred at this temperature for ca 18 h. Thesuspension is then stirred at 0-5° C. for 2 h and the product, isolatedby filtration, washed with EtOAc (5 mL) and dried under vacuum at ca 25°C. to constant weight (2.93 g, 60.2%).

δ_(H) (400 MHz, CDCl₃) ¹H NMR (400 MHz, DMSO-d₆): δ 8.49 (s, 1H), 7.93(d, 1H, J=7.87 Hz), 7.86 (br s, 1H), 7.80-7.75 (m, 2H), 7.68 (d, 1H,J=8.23 Hz), 7.56 (t, 1H, J=7.68 Hz), 7.33 (s, 1H), 7.28 (d, 1H, J=8.42Hz), 7.15 (br s, 1H), 7.06 (s, 1H), 5.94 (q, 1H, J=6.10 Hz), 3.52 (s,2H), 2.45-2.20 (m, 8H), 2.13 (s, 3H), 1.74 (d, 3H, J=6.22 Hz); MS (ESI):544 [M+H]⁺.

1. A process for preparing a compound of formula (X):

wherein: R³ is F, Cl, Br, alkyl or haloalkyl; R¹⁰ is H or alkyl; or apharmaceutically acceptable salt thereof; comprising the steps of: a)reacting 3-bromo-5-nitrobenzaldehyde:

with an amine of formula:

to prepare a compound of formula (III-a) or a salt thereof:

b) cross-coupling the compound of formula (III-a) or a salt thereof witha compound of formula (IV-a) or a salt thereof:

c) in the presence of a palladium catalyst to prepare a compound offormula (V-a) or a salt thereof:

d) reducing the compound of formula (V-a) or a salt thereof to prepare acompound of formula (VI-a) or a salt thereof:

e) cyclizing the compound of formula (VI-a) or a salt thereof in thepresence of an orthoester and an acid catalyst to prepare a compound offormula (IX) or a salt thereof:

 and f) converting the ester compound of formula (IX), or salt thereofto the amide compound of formula (X).
 2. A process for preparing5-{6-[(4-methylpiperazin-1-yl)methyl]-1H-benzimidazol-1-yl}-3-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxamide:

said process comprising the steps of: a) reacting3-bromo-5-nitrobenzaldehyde:

 with N-methyl piperazine:

 to prepare 1-[3-bromo-4-nitrophenyl)methyl]-4-methylpiperazine or asalt thereof:

b) cross-coupling 1-[3-bromo-4-nitrophenyl)methyl]-4-methylpiperazine ora salt thereof with methyl5-amino-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylateor a salt thereof:

in the presence of a palladium catalyst to prepare methyl5-({5-[(4-methyl-1-piperazinyl)methyl]-2-nitrophenyl}amino)-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylateor a salt thereof:

c) reducing methyl5-({5-[(4-methyl-1-piperazinyl)methyl]-2-nitrophenyl}amino)-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylateor a salt thereof to prepare methyl5-({2-amino-5-[(4-methyl-1-piperazinyl)methyl]phenyl}amino)-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylateor a salt thereof:

d) cyclizing methyl5-({2-amino-5-[(4-methyl-1-piperazinyl)methyl]phenyl}amino)-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylateor a salt thereof to prepare methyl5-{6-[(4-methyl-1-piperazinyl)methyl]-1H-benzimidazol-1-yl}-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylateor a salt thereof:

 and e) reacting methyl5-{6-[(4-methyl-1-piperazinyl)methyl]-1H-benzimidazol-1-yl}-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylateor a salt thereof with formamide and a base to prepare5-{6-[(4-methylpiperazin-1-yl)methyl]-1H-benzimidazol-1-yl}-3-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxamide.3. The process according to claim 2, wherein said steps c) of reducingand d) of cyclizing are combined.
 4. The process according to claim 2,wherein: said step a) comprises preparing1-[3-bromo-4-nitrophenyl)methyl]-4-methylpiperazine HCl; said step b)comprises cross-coupling1-[3-bromo-4-nitrophenyl)methyl]-4-methylpiperazine HCl with methyl5-amino-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylateor a salt thereof in the presence of a palladium catalyst to preparemethyl5-({5-[(4-methyl-1-piperazinyl)methyl]-2-nitrophenyl}amino)-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylateHCl; said step c) comprises reducing methyl5-({5-[(4-methyl-1-piperazinyl)methyl]-2-nitrophenyl}amino)-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylateHCl to prepare methyl5-({2-amino-5-[(4-methyl-1-piperazinyl)methyl]phenyl}amino)-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylateHCl; said step d) comprises cyclizing methyl5-({2-amino-5-[(4-methyl-1-piperazinyl)methyl]phenyl}amino)-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylateHCl to prepare methyl5-{6-[(4-methyl-1-piperazinyl)methyl]-1H-benzimidazol-1-yl}-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylateHCl; and said step e) comprises reacting methyl5-{6-[(4-methyl-1-piperazinyl)methyl]-1H-benzimidazol-1-yl}-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylateHCl with formamide and sodium methoxide to prepare5-{6-[(4-methylpiperazin-1-yl)methyl]-1H-benzimidazol-1-yl}-3-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxamide.